Sulphonic halides



Patented Feb. 14, 1939 UNITED STATES 2,147,346 PATENT orrlcs SULPHONIOHALIDES Treat B. Johnson, Bethany, -0onn., alsignor to Bohm a BaasCompany, Philadelphia, Pa., a corporation of Delaware No Drawing.

Application April 10, 1037;

Serial No. 136,129

12 Claims.

.my prior application Serial No. 72,983, filed April The invention isparticularly advantageous for the production of alkyl and aralkylsulphonyl halides and sulphonic acids, but is also applicable to theproduction of aryl sulphonyl halides and sulphonic acids, cycloalkylsulphonyl halides and sulphonic acids, heterocyclic sulphonyl halidesand sulphonic acids, etc., as well as derivatives of such compounds,such as the corresponding sulphonamides, etc.

Methods heretofore proposed for the production of alkyl or aralkylsulphonic acids have involved either the reaction of a sulphite, such assodium or ammonium sulphite, with an alkyl or arallwl halide, or haveinvolved the oxidation of a mercaptan or a metal salt of a mercaptan bya strong oxidizing agent. Both of these methods of production haveserious objections, and involve numerous diiiiculties.

Alkyl and aralkyl sulphonyl chlorides have heretofore been produced bythe action of phosphorus pentachloride on the corresponding sulphonicacid. The use of phosphorus pentachloride in any commercial operationis, of course, highly objectionable, and the preparation of sub phonylchlorides by this method is also expensive, as it involves theproduction of the sulphonic acid first. Furthermore, it is known thatsome alkyl and arallwl sulphonyl chlorides undergo partial decompositionor dissociation in the presence of phosphorus pentachloride, givingsulphur dioxide and the corresponding alkyl and aralkyl chloride. Othersulphonyl halides, such as sulphonyl bromides, have never been producedin a practical manner heretofore. When a sulphonic acid is reacted withphosphorus pentabromide the corresponding bisulphide is often the majorprodnot of the reaction, rather than the desired sulphonyl bromide.

The present invention provides a method by which the various sulphonylhalides and sulphonic acids may be made commercially available, in whichno dangerousor unpleasant materials are used, and in which the operatingconditions involved in carrying out the process are simple to maintain.

The invention in its broader aspect comprehends the formation of asulphonyl halide from a pseudothiourea or pseudothiourea salt byexposing an aqueous solution or suspension of the pseudothiourea orpseudothiourea salt to the sulphonyl halide,

action of a halogen, as shown in the following equation:

RSC\ +X+Hs0 o nsoix-i-xc N in which R represents an alkyl, aralkyl,aromatic, cycloalkyl or heterocyclic residue and X represents a halogen.This reaction is general, and is applicable to compounds having thepseudothiourea residue:

in which R represents an alkyl, an aralkyl, an airy], cycloalkylheterocyclic or other residue, substituted or unsubstituted, linkedthrough a carbon atom to the sulphur, whether the three bonds shown onthe nitrogen atoms are attached to hydrogens, to hydrocarbon radicals,other residues, or are part of a cyclic or ring structure. The reactionapparently involves the oxidation of the sulphur atom followed by asplitting of the bond between the sulphur and the carbon of thepseudothiourea residue, with formation of the without any intermediateformation 0! a mercaptan or other undesired product.

From the sulphonyl halide derivatives so produced, the correspondingsulphonic acids are prepared by hydrolysis as by warming in water, andtheir metallic salts by reaction in aqueous solution, e. g., with sodiumor potassium hydroxide, or other bases, either organic or inorganic,particularly the nitrogen bases.

While the invention may be used generally for the production ofsulphonyl halides and sulphonic acids from compounds containing thecarbon linked pseudothiourea residue described above, it is particularlyadvantageous for the production of sulphonyl halides and sulphonic acidsfrom salts of alkyl and aralkyl pseudothioureas, as these are the mostsimply prepared from commercially available materials.

As starting materials for the preparation of the alkyl and aralkylpseudothioureas and their salts, it is preferable in some cases to usethe corresponding alkyl or aralkyl alcohol, and thiourea. The thioureais dissolved in the alcohol, using heat, as from a water bath. ifnecessary, and the resulting solution is treated with an excess of anacid such as hydrochloric acid and allowed to digest until the formationof the pseudothiourea hydrochloride is complete. This requires'digestionfor a variable time, depending on the reactivity of the respectivealcohol. After digestion, the excess alcohol is distilled off and a saltof the allgvlor aralkyl pseudothiourea corre- The slim a d ylpseudoluourea salts may also be produced by the action of thiourea onalkyl or arakyl halides, sulphates, etc., such as ethyl chloride orbenzylchloride in the known manner.

From the salts of alkyl and aralkyl pseudothioureas so produced, theproduction of the corresponding sulphonyl halides in accordance withthis invention is simple. It is merely necessary to pass through anaqueous solution of the pseudothiourea salt a halogen, such as chlorineor bromine, or, more broadly,-to subject an aqueous solution of thepseudothiourea salt to the action of a free halogen. The halogen reactswith the salt to oxidize the sulphur atom and to split the oxidizedpseudothiourea residue, thus producing directly the desired sulphonylhalide, which is precipitated and usually is easily purified. Duringthis operation, the reaction mixture should be maintained relativelycool, particularly when labile products, such as sulphonyl bromides areproduced, to avoid decomposition. For the production of sulphonylchlorides, the mixture is advantageously maintained below 15 0.; forsulphonyl bromides, below 5 C.

Certain precautions must be observed, however, in the preparation oi.the sulphonyl halide to obtain a pure product. For example, it it isdesired-to produce a sulphonyl chloride, then the pseudothiourea saltwhich is used should either be the hydrochloride or should be the saltof some other acid which does not contain a reactive halogen other thanchlorine. If salts of alkyl or aralkyl pseudothioureas with acids suchas hydrobromic acidare used, the chlorine used for the production or thesulphonyl chloride reacts with the bromine in the hydrobromic acid toset free bromine, with the result that instead or the sulphonyl chloridebeing produced, a mixture oi. sulphonyl chloride and sulphonyl bromideis produced. In some circumstances such a mixture may be desired, andmay be readily produced in this manner, but in normal circumstances apure product, such as the sulphonyl chloride or the sulphonyl bromide,is desired, and care should be taken that any undesired halogen is notintroduced into the product because of its presence in thepseudothiourea salts.

Similarly, for the production or a sulphonyl bromide, the use ofhydrochloric acid salts of pseudothiourea should be avoided, as ii.hydrochloric acid salts are used, the desired sulphonyl bromide will becontaminated with traces of sulphonyl chloride. Thus for the productionor sul phonyl bromide, either the hydrobromide of the desiredpseudothiourea should be used, or else such salts as the acetate or thesulphate should be used.

Salts of other acids than the halogen acids or alkyl and aralkylvpseudothioureas may be readily produced. A preferred method ofproducing these salts is by the reaction of-a hydrohalide or the desiredpseudothioureayith an alkali metal salt, such as potassium or sodiumacetate. In such a procedure, the alkali metal halide is producedsimultaneously with the desiredsalt oi the pseudothiourea. For example,it an aqueous solution or a hydrohalide of an alkyl pseudothiourea betreated with potassium acetate, the corresponding potassium halide andalkyl pseudothiourea acetate is produced. From this acetate, any of thedesired alkyl sulphonyl halides may be produced directly by subjectingthe acetate to the action of the desired halogen in water solution. I

Other salts or alkyl and aralkyl pseudothioureas may be produced inother manners, forexample, from the reaction of thiourea with alkyl oraralkyl nitrates, thiocyanates, sulphates, etc. For example, fromdiethyl sulphate, or other alkyl or aralkyl sulphates, ethylpseudothiourea sulphate, or other alkyl or aralkyl pseudothioureasulphates, may be produced. The sulphates so produced may be subjectedto the action of a halogen in aqueous solution with production of thecorresponding alkyl or aralkyl sulphonyl halides, which-may be producedby proper purification in pure state without contamination by othersulphonyl halides.

The invention will be further illustrated by the following examples,although it is not limited thereto (parts by weight) Example 1n-Butylsulphonyl chloride from n-butyl alc0hol.60 parts of n-butyl alcohol and7.6 parts of powdered thiourea are admixed, and to the resultingsolution is added an amount of hydrochloric acid slightly in excess ofthe amount required for equal molecular proportions with the thiourea.The solution is then heated on a steam bath for 3 or 4 days, or until asample of the solution gives little or no silver sulphide when testedwith ammoniacal silver nitrate. The excess n-butyl alcohol is thenremoved under re-' duced pressure on a steam bath and the viscous.residue resulting dissolved in 75 parts of warm water. This solutioniscooled and treated with chlorine while maintained below 15 C. Bullicientchlorine is added to saturate the aqueous layer, the saturation beingshown by the characteristic green color oi! the saturated aqueous layer,and the n-butyl sulphonyl chloride which separates is taken up in ether.The ether extract is washed with dilute sodium bisulfite solution anddried over calcium chloride. The ether is removed. To further purify thesulphonyl chloride, it may be distilled under reduced pressure. Theproduct has a boiling point of '79 to 81 C. (9 mm.). The reactions whichtake place in this procedure are shown in the following equation:

From the n-butyl sulphonyl chloride produced as .described above, thecorresponding sulphonicacid, n-butyl sulphonic acid, may be produced byhydrolyzing the sulphonyl chloride in boiling water with the productionof hydrochloric acid and n-butyl sulphonic acid. The hydrochloric acidand excess water may be readily removed by evaporation, and thesulphonic acid obtained. The sodium and potassium salts of the sulphonicacid may be obtained by interaction of the n-butyl sulphonyl chloridewith sodium and potassium hydroxide in aqueous solution.

Example 2-Ethul sulphonyl chloride from ethyl sulphate.33 parts ofdiethyl sulphate and 30partsofthlmreaarewarmedonasteambath untilsolution is complete and a vigorous reaction takes place. The reaction,if it becomes too vigorous, may be modified by cooling the mixture.After the reaction is finished, alcohol is added and the mixture isfurther heated for about hour to insure completion of the reaction. Thesolid ethyl pseudothiourea sulphate which is formed is filtered oil anddried.

15.4 parts 0! the ethyl pseudothiourea sulphate are dissolved in partsof water and the solution is cooled in an ice bath, and treated withchlorine while maintained below 15 C. The addition of chlorine iscontinued until the aqueous layer is distinctly green with excesschlorine. The ethyl sulphonyl chloride separates as an oil, and, afterits separation is complete, is mechanically separated or the mixture isextracted with ether and the ether extract washed with dilute sodiumbisulphite solution and dried over calcium chloride. The ether isremoved and the ethyl sulphonyl chloride distilled under reducedpressure to purify it. It boils at 71-72 C. (12 mm).

The reactions which take place when this procedure is followed are shownin the following equation:

CzHsS 0:0]

and a sample of the solution gives no precipitate of silver sulphidewith ammoniacal silver nitrate. The ethyl alcohol is distilled off underreduced "pressure and the n-heptyl pseudothiourea hydrobromide formed isallowed to crystallize.

20 parts of this hydrobromide are dissolved in '75 parts of hot water,and the resulting solution is treated with a hot solution of 35 parts ofpotassium acetate in 40 parts of water. The resulting mixture is cooled,and the precipitated n-heptyl pseudothiourea acetate is filtered off andpurified by recrystallization from water. 12 parts of the n-heptylpseudothiourea acetate are dissolved in parts of water and 2 parts ofconcentrated hydrochloric acid are added. The resulting solution iscooled and treated with chlorine at a temperature below 15 C. After then-heptyl sulphonyl chloride is completely separated, the mixture isextracted with ether. the ether extract is washed with dilute sodiumbisulphite, and dried over calcium chloride. The ether is removed andthe residue, consisting of n-heptyl sulphonyl chloride, is distilledunder reduced pressure to purify it. The product has a boiling point of126 to 129 C. (11 mm).

The reactions which take place when this procedure is followed are shownin the following equation:

fl -C1HuBr+C 8 (N31):

The corresponding n-heptyl sulphonic acid may be obtained from thesulphonyl chloride by hydrolyzing with water.

Example '4--Eth1!l sulphonyl bromide from ethyl bromide-Ethyl bromideand thiourea in equal molecular proportions are heated together i inethyl alcohol. When the thiourea is all dissolved, and a sample of thesolution gives no silver sulphide with ammoniacal silver nitrate, thealcohol is removed under reduced pressure and the residue is allowed tocrystallize; It is ethyl pseudothiourea hydrobromide.

18.5 parts of this ethyl pseudothiourea hydrobromide are dissolved in200 cc. of water. The solution is cooled, and treated with 125 parts ofbromine. The bromine is added over a period of about of an hour withvigorous stirring and while maintaining the temperature below 5' C.After the addition of bromine is complete, the reaction mixture isstirred at 5 C. or lower for about 3 hours. The precipitated ethylsulphonyl bromide is taken up in ether and the excess bromine removedfrom this extract by washing with dilute sodium bisulphite, preferablyin a series of washing operations with small portions of the bisulphitesolution. The extract is then washed with water, dried and the etherdistilled off. The resulting purified ethyl sulphonyl bromide is thendistilled under reduced pressure to purify it. It boils at 8486 C. (18mm.).

The reactions which occur when this procedure. is followed are shown inthe following equation:

H20 .HBr-l-Br CgHgSOzBl' Example 5Benzylsulphonyl chloride frombnzylchloride.12.6 parts of benzylchloride and 7.6 parts of powderedthiourea are warmed together on a steam bath until a vigorous reactiontakes place. mixture is heated for a few minutes and then is dissolvedin parts of water. The resulting solution is cooled below 15 C. and istreated with chlorine with continued cooling, and while maintaining thetemperature below 15 C. The addition of chlorine is continued until thereaction mixture has a distinct green color from the excess chlorine.The solid benzylsulphonyl chloride which separates is filtered oil andthe filtrate is tested for the completeness of the reaction by furtheraddition of chlorine. The separated benzylsulphonyl chlorideis driedover' sulfuric acid and recrystallized from benzene. It has a meltingpoint of 91-92" C.

The reactions which take place when this procedure is followed aresimilar to those shown for the production of ethyl sulphonyl bromidefrom ethyl bromide in Example 4 above.

Benzylsulphonic acid is produced from benzylsulphonyl chloride byhydrolysis with water, but

When the reaction subsides, the

the sulphonyl chloride undergoes partial decomposition during thishydrolysis with evolution of sulphur dioxide.

Example 6-Ethylsulphonyl chloride from 2- ethylmercapto 4 chloro 5carbethoxypm'imidine.-6.3 parts of 2-ethylmercapto-4-chloro-5-carbethoxypyrimidine are suspended in 60 parts of water at about {ill-40C. and chlorine is rapidly passed into the mixture. When the oil formedis completely separated. the mixture is shaken with petroleum ether, andthe resulting extract fractionated at reduced pressure. The fractionboiling at 68-74 C./ 18 mm. is taken as ethyl sulphonyl chloride, as itformed sulphonamid (ethyl sulphonamid), M. P. 59-60 C. and ammoniumethylsulphonate, M. P. 208-209 C.

CHiCOOC8|CHrCl+CB(NHr)a -v CHrCOOCHgCHsSC a The reaction involved inthis process may be represented by the graphic equation:

N=C 01. (l: 5 H10 CiHiSI C0:CaHri-Cla CrHrBOsCl In the followingexamples, processes which CICHiCHaO CHQCHIOI+03(NHI)Q -v C(CHICHaBC havebeen described in detail in the previous examples will merely beoutlined, these examples serving to illustrate the broad scope of theinvention, it being understood that the processes in general are similarto those previously described.

Example 7--Dodecyl sulphonyl chloride from dodecyl chloride.-Dodecyl'pseudothiourea hydrochloride is produced from dodecyl chloride andthiourea following the procedure outlined-in previous examples, and isdissolved in water and treated with chlorine while maintained belowabout 15 C. The dodecylgsulphonyl chloride obtained melts at 42-43 C.gvhile the corresponding sulphonamid, readily obtained, melts at 93-94C.

The corresponding hexadecyl sulphonyl chloride, melting point 53-54" C.,and sulphonamid, melting point 96.5-97.5 C. are readily obtained in asimilar manner from hexadecyl chloride.

Example 8Sec. butyl sulphonyl chloride from sec. butyl alc0hol.Sec.butyl alcohol and thiourea are reacted in the presence of hydrochloricacid, following the procedure previously outlined, and the resultingproduct is treated in aqueous solution with chlorine, with theproduction of sec. butyl sulphonyl chloride, boiling point 89-905 C./19mm.

Example 9Cuclohexylsulphonyl chloride from cyclohexyl alcohoL-Cyclohexyalcohol and thiourea are reacted as described in the presence ofhydrochloric acid, and the resulting product is treated in aqueoussolution with chlorine, with the formation of cyclohexyl-sulphonylchloride, boiling point 123-124. C./6 mm. The corresponding sulphonamidemelts at 94-95 C.

Example 10-p-Nitrobenzylsulphonyl chloride from p-nitrobenzylchloride.p-Nitrobenzyl chloride is reacted with thiourea as described,and the resulting p-nitrobenzyl pseudothiourea hydrochloride is treatedin aqueous solution with chlorine, with the formation ofp-nitrobenzylsulphonyl chloride, melting point 93-94 C. Thecorresponding sulphonamide has a melting point of 205 C.

Example 11--Tetrahydrojur/uryl sulphonyl chloride fromtetrahydrofllrlaryl chloride.- Tetrahydrofurfuryl chloride is reactedwith thiourea as described, and the resulting tetrahydroiurfurylpseudothiourea hydrochloride is treated in aqueous solution withchlorine, with the production of tetrahydrofurfuryl sulphonyl chloride,boiling point -118 C./5 mm. There is considerable decomposition duringthe chlorination.

Example 12B-acctoxyethyl sulphonyl chloride from B-dcetozflethylchlorideFB-acetoxyethyl chloride and thiourea are reacted as described,and the resulting product is treated in aqueous solution with chlorine,with the formation of B-acetoxyethyl sulphonyl chloride, boiling point101-103 C./4 mm., according to the equation:

N H H1O .HCH-Oh CHrCOOCHaCHaBOaCl Example 13.B-B'-disulphonyl chlorideethyl ether from B-B'-dichlorethyl ether.'.B-B'-dichloroethyl ether andthiourea are reacted as described and the resulting product treated inaqueous solution with chlorine, with the production of crudeBv-B'-disulphonyl chloride ethyl ether, according to the equation:

Successful purification of this product by distillation has not yet beenaccomplished.

In addition to the sulphonyl halides and sulphonic acids described inthe examples, numerous other sulphonyl halides and sulphonic acids maybe prepared in accordance with the present invention. Among the alkylsulphonyl halides which may be readily produced are the lower alkylcompounds such as the methyl, ethyl, the isomeric propyls, butyls,amyls, hexyls, heptyls, etc., as well as the higher alkyl sulphonylhalides such as the cetyl, oleyl, stearyl, etc. various aralkylsulphonyl halides and the sulphonic acids may be readily prepared.Included among the arakyl sulphonyl halides which may be readilyprepared are the benzyl, phenyl ethyl, nitrobenzyl, other substitutedbenzyls, etc. For the production of such sulphonyl halides and sulphonicacids, the starting materials may be either the corresponding alcoholsor corresponding esters, such as sulphates, chlorides, nitrates,acetates, etc., although in general it will be found more advantageousto the alcohols for the production of the lower alkyl and cycloalkylderivatives and to use the salts for the production of the higher alkyl,heterocyclic and aralkyl derivatives.

The aralkyl derivatives, in addition to having the sulphonyl halidegroup or the sulphonic acid group attached to the alkyl chain, may alsobe substituted in the aromatic or cyclic nucleus. Substituents such assulphonic acid groups, or halogen groups, or other groups, in thearomatic or cyclic nucleus in no way interfere with the process of thepresent invention for the production of sulphonyl halides and sulphonicacids, either in the production of the intermediate pseudothioureaderivatives, or the production of the sulphonyl halides and sulphonicacids from these intermediates.

The invention, as previously pointed out, is also applicable to theproduction of heterocyclic, cycloalkyl and aryl sulphonyl halides andsul- Also, the' anus-1e compounds, however, cannot be prepared in themanner described above for the production of alkyl and aralkylpseudothiourea compounds, but must be prepared in some other manner, asby the addition of a thiophenol to a cyanamid.

In the process as hereinbefore described. the hydrolysis of thesulphonyl halides to produce the corresponding sulphonic acids hasfollowed the isolation of the sulphonyl halides; but such isolation isnot always necessary, as many of the sulphonic acids may be produced byhydrolysis of the sulphonic halides without their intermediateseparation or isolation from the reaction mixture in which they areproduced.

While the invention has been described with particular reference to theproduction 01 sulphonyl chlorides and sulphonyl bromides, it alsoincludes the production of homologous sulphonyl fluorides and sulphonyliodides, and while it is particularly advantageous for use in theconversion of alkyl or aralkyl pseudothiourea salts to correspondingsulphonyl halides by the action of a halogen, it is also applicable tothe production of sulphonyl halides from other compounds in which apseudothiourea residue is connected to an alkyl group through thesulphur atom. Included in this class of compounds are compounds such asalkyl or aryl derivatives of alkylpseudothioureas, in which the hydrogenatoms linked with the nitrogen are replaced by aliphatic or aromaticradicals, as well as heterocyclic compounds, in which the pseudothioureanucleus is part of a ring structure.

I claim:

1. The process or producing sulphonyl halides which comprises subjectingan aqueous solution of a compound of the formula ganic nucleus of thedesired compound attached to a pseudothiourea residue through a carbonatom to the sulphur atom of the pseudothiourea residue, to the action ofa halogen.

3. The process of producing compounds of the formula RSOzX inwhich R isan organic radical linked to the so=x radical through a carbon atom andX is a halogen which comprises subjecting a compound having the organicradical of the desired compound attached to the sulphur atom or apseudothiourea residue through a carbon atom to the action of a halogenin the presence of water.

4. The process 01' producing sulphonyl halides which comprisessubjecting a compound having an organic radical attached through acarbon atom to the sulphur or a pseudothiourea residue to the action ora halogen in the presence of water.

5. The process of producing sulphonyl halides which comprises subjectinga compound having the radical asc N: in which R is an organic radicalattached to the sulphur atom through a carbon atom to the action of ahalogen in the presence of water.

6. The process of producing sulphonyl halides which comprises subjectingan aqueous solution 0! a salt of a pseudothiourea derivative having anorganic radical attached through a carbon atom to the sulphur atom ofthe pseudothiourea residue to the action of a halogen.

'7. The process of producing compounds of the formula RSOsX in which R.is an organic radical and X is a halogen which comprises subjecting anaqueous solution or a salt of a compound of the formula to the action ofa halogen.

8. The process of producing sulphonyl halides which comprises subjectinga compound or the formula a s o N in which R. is an organic radical and.the

BBO

in which R is an organic radical attached to the sulphur atom through acarbon atom with an acid selected from the group consisting o1hydrobromic and non-halogen containing acids to the action of bromine.

10. The process of producing sulphonyl bromides which comprisessubjecting an aqueous solution of a salt of a compound of the classconsisting oi S-alkyl, B-aryl and S-aralkyl pseudothioureas with an acidselected from the group consisting of hydrobromic and non-halogen-containing acids to the action of bromine.

11. The process 01' producing alkyl sulphonyl bromides which comprisessubjecting an aqueous solution of a salt of an S-alkyl pseudothioureawith an acid selected from the group consisting of hydrobromic andnon-halogen containing acids to the action of bromine.

12. The process oi producing aralkyl sulphonyl bromides which comprisessubjecting an aqueous solution of a salt oi an S-aralkyl pseudothioureawith an acid selected from the group consisting of hydrobromic andnon-halogen containing acids to the action oi bromine.

mar B. JOHNSON.

